Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)



Research Advisor

Carol L. Thompson, Ph.D.


Ann K. Cashion, Ph.D. David A. Kuhl, Pharm.D. Jim Y. Wan, Ph.D. Charles R.Yates, Pharm.D., Ph.D.


Critical Care, Health Care Associated Infections, Polymorphisms, Sepsis, Systemic Inflammation


The purpose of this study was to determine the impact of baseline systemic inflammation (pro‑inflammatory cytokine, anti‑inflammatory cytokine, and their ratio), genetic variability, and environment on the development of health care associated infections (HAI) among sepsis patients during their ICU stay (up to 28 days).

Methods: A prospective observation study was conducted at the Veterans Affairs Medical Center in the Medical Intensive Care Unit over an 18 month period. A total of 78 patients were enrolled within 72 hours of presenting to the ICU with sepsis. Patient were excluded if they were receiving immunosuppressants (chemotherapy or greater than one mg/kg of prednisone or equivalent dose), immunosuppressed (AIDS, cancer), or had liver failure (Child Pugh category C or higher). Baseline plasma and buccal swabs were collected. Patients were followed prospectively through their ICU stay (or for a maximum of 28 days) for the development of HAI as defined by CDC guidelines. Primary variables included baseline IL‑6 and IL‑10 levels, IL‑6 SNP rs1800795, IL‑10 SNP rs1800896, APACHE II, invasive devices, and development of HAI.

Results: A total of 17 HAI were identified with 64% caused by Candida. There were no significant differences in levels of pro‑inflammatory cytokine, anti‑inflammatory cytokine, or their ratio among subjects who did and did not develop at least one HAI during their ICU stay. There were also no significant differences in rs1800795 or rs1800896 genotypes for those who did and did not develop HAI; however, racial differences were detected in genotypes among white and black patients with sepsis who did and did not develop HAI. There was a significant difference in rs1800795 genotype among black patients with sepsis who did not develop HAI compared to whites patients with sepsis who did not develop HAI (p = 0.006). Specifically, black patients had a lower CG (17.4% vs. 42.1%) and higher GG (82.6% vs. 42.1%) than white patients. There were no racial differences when comparing white and black sepsis patients who developed HAI (p = 1.0). In a series of Cox regression analyses investigating timing to first HAI among those who did and did not develop HAI during ICU stay, the final model included only APACHE II, cumulative invasive device score, and IL‑6 rs1800795.

Conclusion: This study provides evidence of a genetic risk for development of HAI. Despite best evidenced based practices some patients will develop HAI. Strict aseptic technique is essential to preventing infection. In addition to eliminating invasive devices as quickly as possible, patients with a high severity of illness may need to be isolated to lower their risk. Early administration of antibiotics not only provides prompt treatment for the initial infection but also lowers risk for subsequent infections.




One year embargo expired May 2012